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. 2011:1:67.
doi: 10.1038/srep00067. Epub 2011 Aug 18.

Transplantation of mesenchymal stem cells from young donors delays aging in mice

Jinhui Shen  1 , Yi-Ting Tsai, Nancy M Dimarco, Michael A Long, Xiankai Sun, Liping Tang
Affiliations

Transplantation of mesenchymal stem cells from young donors delays aging in mice

Jinhui Shen et al. Sci Rep. 2011.

Abstract

Increasing evidence suggests that the loss of functional stem cells may be important in the aging process. Our experiments were originally aimed at testing the idea that, in the specific case of age-related osteoporosis, declining function of osteogenic precursor cells might be at least partially responsible. To test this, aging female mice were transplanted with mesenchymal stem cells from aged or young male donors. We find that transplantation of young mesenchymal stem cells significantly slows the loss of bone density and, surprisingly, prolongs the life span of old mice. These observations lend further support to the idea that age-related diminution of stem cell number or function may play a critical role in age-related loss of bone density in aging animals and may be one determinant of overall longevity.

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Figures

Figure 1
Figure 1. Characterization of BMSCs.
(A) BMSCs isolated from EGFP transgenic C57BL/6 mice have typical fibroblast like morphology and exhibit green fluorescence (×20; bar = 100µm). (B) Flow cytometry analysis on BMSCs isolated from Balb/C mice shows the majority of cells are CD105+, CD29+, CD44+, SCA-1+, CD45−, CD34−. (C) Differentiation capacity of BMSCs isolated from young (1–2 months old) and old (20–24 months old) Balb/C mice. The average ratio of positive cells to total cells in three random ×20 views was calculated as the differentiation rate. N = 5 for each group.
Figure 2
Figure 2. Expression of cellular senescence-related markers 53BP1 and γ-H2AX in BMSCs isolated from young mice (1–2 months old, n = 3) and aged female Balb/C mice (20–24 months old, n = 3).
(A) 53BP1 expression (green) in BMSCs nuclei overlapping with DAPI staining (blue). (B) γ-H2AX expression (green) in BMSCs nuclei overlapping with DAPI staining (blue). (C) Percentage of 53BP1 and γ-H2AX positive cells in BMSCs. *: p = 0.014, **: p = 1.71E-4.
Figure 3
Figure 3. Osteogenic activities and BMSCs migration in bone (n = 7 for each groups).
(A) Prior to radiation, there were few AP+ (pink) cells in bone from old mice while there were significant numbers of AP+ cells in young ones. Immediately following irradiation treatment, few AP+ cells were found in both groups, bar = 100µm. (B) Six months following BMSCs transplantation, the presence of transplanted BMSCs and osteogenic activities were visualized based on anti-GFP (green) and osteocalcin immunohistochemistry staining (red). AP+ cells were also imaged inside or on the edge of bone, bar = 100µm. The density of (C) GFP+ BMSCs and (D) AP+ cells in the bones from mice with either old BMSCs or young BMSCs transplants was determined. **: p<0.01.
Figure 4
Figure 4. Effect of BMSCs transplantation on the life span of Balb/c mice.
(A) The lifespan of mice without (control, n = 10) and with BMSCs transplants from either young (n = 14) or old mice (n = 10). (B) The mean survival time of control animals vs. BMSCs transplanted mice. Kaplan-Meier Log Rank pairwise comparison statistics revealed significant differences of lifespan between the control and young BMSCs transplantation groups (p = 0.009), and between young BMSC transplantation and old BMSCs transplantation groups (p = 0.002). There was no significant difference between the control and old BMSCs transplantation groups (p = 0.846). **: p<0.01.
Figure 5
Figure 5. BMD measurements of Balb/c mice.
(A) The distribution of bone density in untreated mice from 1–33 months (open circles with polynomial treadline, order = 2, n = 99). (B) The distribution of BMD in mice transplanted with BMSCs isolated from young mice (green solid triangles with green dash linear trendline, n = 15) compared with untreated controls (gray open circles with linear trendline, n = 9). (C) The distribution of BMD in mice transplanted with BMSCs isolated from old mice (orange open triangles with orange dash linear trendline, n = 10) compared with untreated controls (gray open circles with linear trendline, n = 9). (D) Direct comparisons of BMD distribution between mice transplanted with young BMSCs (green solid triangles with green dash linear trendline, n = 15) and those with old BMSCs (orange open triangles with orange dash linear trendline, n = 10). (E) Comparison of the averages of BMD at different age ranges.
Figure 6
Figure 6. Micro structure of distal tibia bones from controls and young/old BMSCs transplanted mice 6 months after transplant.
Left images are the three-dimensional (3D) images of mouse tibias, middle images are the X-ray images taken from a KODAK in vivo FX machine, and the right images are the 3D microCT reconstruction images of samples of mouse tibias. Typical bone images from (A) young control mouse, (B) old control mouse, (C) mouse transplanted with young BMSCs, (D) mouse transplanted with old BMSCs, (E) Tabulated parameters and statistical analyses of bone microstructure based on micro-CT analyses, n = 5 for each group.
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